NMR determination of absolute configuration of α-acyloxy ketones

Article abstract of DOI:10.1016/S0957-4166(03)00159-9

Determination of the absolute configuration of several acyclic α-acyloxy-ketones, and δ-ketobutanolides, in the presence of a chiral solvating agent, by low temperature and low concentration ¹H NMR analysis, is reported.

Full text of DOI:10.1016/S0957-4166(03)00159-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 963–966
NMR determination of absolute configuration of a-acyloxy
ketones
Jean-Christophe Jullian,a Xavier Franck,a Shamil Latypov,b Reynald Hocquemillera and
Bruno Figade`rea,*
aLaboratoire de Pharmacognosie, associe´ au CNRS (BIOCIS), Universite´ Paris-Sud, Faculte´ de Pharmacie, rue Jean-Baptiste
Cle´ment, 92296 Chaˆtenay-Malabry, France
bInstitute of Organic & Physical Chemistry of Russian Academy of Sciences, Kazan 420083, Russia
Received 9 December 2002; accepted 4 February 2003
Abstract—Determination of the absolute configuration of several acyclic a-acyloxy-ketones, and d-ketobutanolides, in the
1
presence of a chiral solvating agent, by low temperature and low concentration H NMR analysis, is reported. © 2003 Elsevier
Science Ltd. All rights reserved.
The absolute configuration of non-derivatizable stereo-
genic centers (of both natural products and synthetic
compounds) are difficult to determine. Circular
dichroism1 and chiral chromatographic methods2 (e.g.
HPLC, GC) have been employed for such a task, but a
more readily usable technique such as NMR analysis is
preferable because the equipment is accessible (400
MHz NMR spectrometers are commonly used) and the
experiments are rapid, inexpensive and can be per-
formed with small quantities of material. We have
recently shown that when racemic 5-methylfuran-
tion of their butenolide moiety was determined using
this method (Scheme 1). We then decided to check if
d-ketobutanolides could also be analyzed by our
method. Compounds 3 and 4 were first prepared as
already reported from (S)-glutamic acid5 and then ana-
lyzed in the presence of (R)- and (S)-TFAE 1. When 3
and 4 (0.3 mg, 1 mmol and 1.7 mmol, respectively) were
separately mixed with 17 and 21 equiv. of (R)-1, respec-
tively, at 213 K in CDCl3 and after irradiation at l 2.25
ppm, we observed a singlet for H-5 of 3 and 4 at l
4.738 and 4.760 ppm, respectively.
1
2(5H)one 2 was analyzed by H NMR in CDCl3 solu-
tion at 223 K in the presence of 4 equiv. of
(R)-2,2,2-trifluoro-1-(9-anthryl)ethanol 1 (TFAE), we
were pleased to observe that both the methyl group and
H-5 appeared as two signals (l 1.378/1.331 and 5.095/
5.054 ppm, respectively) corresponding to the (R,S)-
and (R,R)-solvates.3
When 3 and 4 were analyzed under the same condi-
tions, with 17 and 21 equiv. of (S)-1, respectively, the
signals appeared at l 4.775 and 4.786 ppm (correspond-
ing to Dl RꢀS=−0.037 and −0.026, respectively). The
signs of the differences of chemical shifts (DlRꢀS<0) are
in accord with the model showing a first hydrogen bond
between the OH of 1 and the lactone carbonyl of 3 (or
4), and a second hydrogen bond6 between the CaH of 1
and the ring oxygen of the lactone (Scheme 2). Thus,
Furthermore as expected, the chemical shift of the
methyl group of the (R,S) solvate is observed upfield to
that of the (R,R) solvate, as shown by selective irradia-
tion of the H-5 signal, due to the shielding effect of the
aromatic rings. This was predicted by our model.3
Several natural 5-methylfuran-2(5H)ones bearing a
substituent at the
3 position (e.g. annonaceous
acetogenins4) were analyzed and the absolute configura-
* Corresponding author. Tel.: 33 1 46 83 55 92; fax: 33 1 46 83 53 99;
e-mail: bruno.figadere@cep.u-psud.fr
Scheme 1.
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00159-9

964
J.-C. Jullian et al. / Tetrahedron: Asymmetry 14 (2003) 963–966
Table 1. Main conformations energies (PM3 data in kcal/
mol) of the model depicted in Scheme 3
Scheme 2.
the 9-anthryl group of (R)-1 in the solvates has a more
pronounced shielding effect on H-5, while there is less
(or no) effect on this hydrogen with (S)-1. This implies
that these ketones have (S) absolute configuration, as is
known from their stereospecific synthesis from (S)-glu-
tamic acid. We then decided to study the extension of
this method to acyclic derivatives of a-hydroxy-ketones,
compounds possessing ester and ketone functionalities.
NMR differentiation of diastereomeric complexes of
chiral substrates with a chiral reagent could be expected
if a conformational preference of the substrate exists
and there is some preferred complexation site in the
substrate. To estimate this we analyzed the simplest
model shown in Scheme 3, by semiempirical method
(PM3).
mine the overall chemical shift of H-2 of the substrate
and this can preclude NMR determination of absolute
stereochemistry of such substrates. Thus, racemic ben-
zoin acetate 5, -pivalate 6, -benzoate 7, as well as the
tert-butyldimethylsilyl ether of benzoin, 8 were readily
prepared (Scheme 4).
Conformational analysis around three single bonds
(COꢀO, OꢀC2 and C2ꢀC1) was studied. Rotation
around the last two bonds (the first one being dis-
counted because of preferences7) produces six conform-
ers (Table 1) whose major one possessing C2-H gauche
to the ester OꢀCO and the ketone carbonyl trans with
respect to C2ꢀH. In this dominant conformer the two
carbonyl groups are close to each other and both can
be involved in hydrogen bonding (see Scheme 3), with-
out incurring a high energetic barrier. Indeed, these
calculations confirm, as expected, free rotations around
these three single bonds of the molecule. Furthermore,
according to PM3 (as well as pKa considerations), the
carbonyl oxygen of the ester function is more elec-
tronegative than the carbonyl oxygen of the ketone
(−0.39 versus −0.29 (Scheme 3)). Thus, we can expect a
pseudocyclic structure of the complex with a first
hydrogen bond between the hydroxy group of 1 and the
ester carbonyl and a second hydrogen bond between
CaH of 1 and the ketone carbonyl. The orientation of
the 9-anthryl ring in this conformation should deter-
NMR experiments were then carried out by adding
pure (R)- or (S)-TFAE 1 to a CDCl3 solution (1.6–3.2
mM) of the racemic analyte, and the spectra recorded
at 213 K. The signal for H-2 of benzoin acetate 5 (0.5
mg, 1.9 mmol, with 11 equiv. of (S)-1, 5.8 mg) appeared
as two singlets integrating to 1:1 at l 6.816 and 6.777
ppm. When benzoin pivalate 6 was analyzed under the
same conditions, the signal for H-2 also appeared as
two singlets integrating to 1:1 at l 6.729 and 6.690
ppm. However, benzoin benzoate 7, under the same
conditions, showed a broad singlet at 6.996 ppm,
whereas with 19 equiv. of (S)-1, two singlets integrating
to 1:1 at l 6.978 and 6.969 ppm now appeared. When
the tert-butyldimethylsilyl ether of benzoin 8 was ana-
lyzed with 16 equiv. of (R)-1, two singlets, integrating
to 1:1 at l 5.717 and 5.709 ppm, were observed. From
these observations we can conclude that a-acetoxy
ketones or a-pivaloyloxy ketones are best suited for
analysis and e.e. determination by this method. How-
ever, the trialkylsilyl ethers of the corresponding a-
hydroxy ketones could also be used. The a-acetoxy
ketones 9 and 10 were prepared in 43 and 54% yield,
respectively, from racemic and (R)-a-acetoxy mandelic
acid chloride and the a-acetoxy ketones 11–13 were
Scheme 3.
Scheme 4.

J.-C. Jullian et al. / Tetrahedron: Asymmetry 14 (2003) 963–966
965
Scheme 5.
prepared from racemic and (S)-a-acetoxy lactic acid
chloride,8 and the corresponding Grignard reagents9
using a slightly modified published procedure10 (Scheme
5). The results of the NMR experiments are summa-
rized in Table 2. First, the racemic compounds 9–13
were analyzed with (R)-1, showing two signals for H-2.
Then each enantioenriched product was analyzed with
either (S)-1 or (R)-1, under the same conditions. It is of
note that for compounds 11–13, irradiation at l 1.33
ppm (45 dB) was required in order to suppress the
coupling constant between the CH3 and H-2 (thus
giving singlets). In all cases, the analysis of the enan-
tioenriched compounds11 with either (R)- or (S)-1
showed a single signal superimposable with one of the
two signals obtained from the racemic compounds
(when the same number of equivalents of reagent 1 is
used (Fig. 1)).
for compounds 11-13, DdR,S <0 is indicative of (S)
absolute configuration (entries 3–5).
We then studied the two racemic a-benzoyloxyketones
14 and 15 bearing a trifluoromethyl group.12 Again we
were pleased to observe that in the presence of 12 and
15 equiv. of (R)-1, respectively, two signals appeared,
after decoupling of the fluorine atom, for H-2, at l
6.389 and 6.368 ppm, and l 5.601 and 5.590 ppm,
corresponding to Dl= 0.021 and 0.011 for 14 and 15,
respectively (Table 2). By applying our model, we can
predict that the signals appearing at higher field corre-
spond to H-2 of the (R)-14 and (R)-15 compounds,
whereas the downfield signals correspond to H-2 of the
(S)-14 and (S)-15 enantiomers. In other words, DlR,S
<0 are in agreement with these predictions (these results
are in accord with precedent results, but because of
inversion of the CIP priority orders, the signs of DlR,S
are inverted compare to compounds 9 and 10).
Table 2. Dl H-2 of ketones 9–15 with either (S)- or (R)-1
Entry
Substrate
DlR,S (n equiv. of Absolute config. (ee)
1)
1
2
3
4
5
6
7
9
10
11
12
13
14
15
+0.011 (13)
+0.012 (13)
−0.022 (18)
−0.024 (21)
−0.136 (24)
90.021 (12)
90.011 (15)
R (\96)
R (\96)
S (\96)
S (\96)
S (\96)
– (0)
Figure 1. Partial 1H NMR spectra: (a) ( )-9 and 13 equiv.
(R)-1; (b) (R)-9 and 13 equiv. (R)-1; (c) (R)-9 and 15 equiv.
(S)-1.
– (0)
From the above calculations, the first hydrogen bond
should occur between the hydroxy group of 1 and the
carbonyl group of the ester functions and the second
hydrogen bond between the CaH of 1 and the carbonyl
oxygen of the ketones (Scheme 5). The observed results
are all in accord with this model, which predicted that
for compounds 9 and 10 DdR,S >0 (entries 1 and 2) is
indicative that H-2 is on the same side than the CF3
group in the solvate formed with (R)-1, and thus in
accord with (R) absolute configuration of the stereo-
genic centers (through the CIP priority order), whereas
By applying the same model, as shown in Scheme 5, to
compounds 5–8, we can predict that the signals appear-
ing upfield correspond to the (S,S) or (R,R) solvates,
whereas the downfield signals correspond to the (R,S)
or (S,R) solvates.
In conclusion, this study shows that our very efficient
1H NMR method allows the determination of the abso-
lute configuration of cyclic and acyclic a-acyloxy-
ketones, as well as their e.e.s. The observed DlR,S
values are usually greater than 0.01 ppm (0.01–0.136

966
J.-C. Jullian et al. / Tetrahedron: Asymmetry 14 (2003) 963–966
ppm), which is well above the experimental resolution
and is similar to the differences in chemical shifts
obtained with Mosher’s esters.13 Thus, we propose that
in order to measure the e.e. of a-hydroxyketones, their
corresponding acetates should be prepared and then
analyzed by our method, instead of preparing the
Mosher’s esters at the risk of performing a kinetic
resolution and thus obtaining false results. This tech-
nique extends the use of Pirkle’s reagent14 (currently
employed for e.e. and absolute configuration determi-
nations of cyclic compounds such as lactones14 and
lactams15) because of the crucial effect of low tempera-
ture and low concentration, allowing one to apply this
method to other natural products as well.
9. Typical non-optimized procedure: To a solution of car-
boxylic acid chloride (15 mmol) in THF (10 mL) at
−78°C was added the corresponding Grignard reagent (17
mmol). After 3 h of stirring, the mixture was hydrolyzed
with saturated NH4Cl solution. The aqueous solution
was extracted with EtOAc. The organic layers were com-
bined, dried over MgSO4, filtered and evaporated. The
crude mixture was purified by flash-chromatography
(cyclohexane/EtOAc) to afford the corresponding
ketones: 9 (43%), 10 (54%), 11 (25%), 12 (30%), 13 (10%).
10. Cahiez, G.; Metais, E. Tetrahedron Lett. 1995, 36, 6449–
6452.
11. Data for compound 9: [h]D=−191 (c 0.75, CHCl3); 1H
NMR (200 MHz, CDCl3) l ppm: 7.39 (brs, 5H), 5.97 (s,
1H), 2.39 (m, 2H), 2.18 (s, 3H), 1.49 (m, 2H), 1.22 (sex.,
2H, J=7.2 Hz), 0.81 (t, 3H, J=7.2 Hz); 13C NMR (50
MHz, CDCl3) l ppm: 203.97, 170.18, 133.33, 129.18,
128.95, 128.13, 80.65, 38.30, 25.27, 21.99, 20.61, 13.59;
10: [h]D=−128 (c 0.78, CHCl3); 1H NMR (200 MHz,
CDCl3) l ppm: 7.46 (brs, 5H), 6.03 (s, 1H), 2.45 (m, 2H),
2.24 (s, 3H), 1.56 (m, 2H), 1.27 (brs, 18H), 0.94 (t, 3H,
J=6.7 Hz); 13C NMR (50 MHz, CDCl3) l ppm: 204.05,
170.24, 133.37, 129.27, 129.00, 128.19, 80.70, 38.66, 31.88,
29.58, 29.51, 29.35, 29.30, 29.20, 28.91, 23.25, 22.65,
20.68, 14.05; 11: [h]D=−30 (c 1.09, CHCl3); 1H NMR
(200 MHz, CDCl3) l ppm: 5.08 (q, 1H, J=7.1 Hz), 2.45
(m, 2H), 2.12 (s, 3H), 1.55 (m, 2H), 1.38 (d, 3H, J=7.1
Hz), 1.34 (m, 2H), 0.90 (t, 3H, J=7.2 Hz); 13C NMR (50
MHz, CDCl3) l ppm: 207.74, 170.28, 74.58, 37.85, 25.22,
22.22, 20.67, 16.09, 13.74; 12: [h]D=−20 (c 0.71, CHCl3)
1H NMR (200 MHz, CDCl3) l ppm: 5.09 (q, 1H, J=7.1
Hz), 2.45 (m, 2H), 2.13 (s, 3H), 1.57 (m, 2H), 1.39 (d, 3H,
J=7.1 Hz), 1.26 (brs, 18H), 0.88 (t, 3H, J=6.7 Hz); 13C
NMR (50 MHz, CDCl3) l ppm: 207.68, 170.25, 74.58,
38.15, 31.85, 29.56, 29.39, 29.33, 29.27, 29.12, 23.13,
22.62, 20.65, 16.09, 14.02; 13, see: Babudri, F.; Fian-
danese, V.; Marchese, G.; Punzi, A. Tetrahedron, 1999,
55, 2431–2440.
Acknowledgements
We thank D. Deschamps for her technical help, Drs. D.
Bonnet-Delpon, B. Crousse and J. Iskra for generous
gifts of 14 and 15, and M. Ourevitch for her help in the
NMR experiments.
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